This application aims to investigate the pharmacologic mechanisms that underlie experimental painful neuropathy. Sciatic nerve ligation in the rat is an experimental neuropathy that is associated with the development of behavioral hyperalgesia. The neurotransmitter systems that develop and mediate this hyperalgesia are unknown but may include NMDA or opioid receptor-mediated effects. These effects will be investigated at the spinal level using NMDA and opioid receptor agonists and antagonists. Knowledge of an NMDA or opioid receptor-mediated effect in the development or mediation of experimental neuropathy may lead to better treatment for human conditions of painful neuropathy. The application also aims to develop a new model of experimental painful neuropathy in which herpes vectors are used to cause cell-specific injury to the nervous system. This injury may be associated with the development of behavioral hyperalgesia. The pharmacologic mechanisms which underlie such hyperalgesia may be similar to those that contribute to hyperalgesia following sciatic nerve ligation, and will be investigated using similar methods.